Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of signal-transducing molecules known. 7TMRs convey signals for light and many extracellular regulatory molecules, such as, hormones, growth factors and neurotransmitters, that regulate every cell in the body. Dysregulation of 7TMRs has been found in a growing number of human diseases and 7TMRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, understanding how 7TMRs function is an important goal of biological research. We have used receptors for thyrotropin-releasing hormone (TRH) (TRH-Rs) and for thyroid-stimulating hormone (TSH-R) as model 7TMRs to study their structure and function. During this year, we studied several new aspects of the structure and function of these receptors. 1) We used a novel small molecule agonist that we discovered to better understand the structure-function relationship and the signaling properties of the TSH-R. Specifically, we showed that although several mutant receptors that caused hypothyroidism in patients could not be activated by TSH, which binds to the large extracellular domain, but could be activated by a small molecule agonist, which binds to the transmembrane domain of TSH-R. This finding conclusively demonstrates the separate domains for binding and signaling. We also showed that these TSH-R mutants signal differently than the normal TSH-R. 2) We showed that the TRH-R signals persistently, that is, it continues to signal after the agonist TRH has been withdrawn. This is a new observation for TRH-R and for several other G protein-coupled receptors that explains how a transient exposure to an agonist can lead to a biologic response that lasts much longer.